# MAP6

## Overview
MAP6, or microtubule-associated protein 6, is a gene that encodes a protein crucial for the stabilization of microtubules and actin filaments, playing a significant role in maintaining cellular structure and facilitating intracellular transport. The protein, categorized as a microtubule-associated protein, is particularly important in neuronal cells, where it contributes to synaptic plasticity and cognitive functions by regulating actin cytoskeleton dynamics within dendritic spines. MAP6 is characterized by unique structural domains, including Mn and Mc modules, which are essential for its microtubule-stabilizing functions, and proline-rich domains that facilitate interactions with other proteins involved in neuronal signaling pathways. The gene's expression and the protein's function are modulated by various post-translational modifications, such as phosphorylation, which influence its interactions and cellular localization. Alterations in MAP6 expression have been linked to neurodevelopmental and psychiatric disorders, including schizophrenia, highlighting its clinical significance in maintaining normal brain function (Volle2012Reduced; Peris2018A; Cuveillier2021Beyond).

## Structure
MAP6, or microtubule-associated protein 6, is characterized by a complex molecular structure that includes several distinct domains contributing to its diverse functions. The protein contains Mn and Mc modules, which are unique to MAP6 and do not share homology with other microtubule-binding domains like those in Tau or MAP1B. These modules are crucial for microtubule stabilization and can induce microtubule coiling, forming helical structures with specific tubulin compaction states (Cuveillier2021Beyond).

MAP6 also features proline-rich domains (PRDs), particularly the PRD 39-57 domain, which is essential for interactions with SH3 domain-containing proteins such as intersectin1 and the p85 subunit of PI3K. This interaction is vital for recruiting and activating signaling pathways that promote axonal growth (Deloulme2015Microtubuleassociated). The protein's N-terminal domains contain cysteine residues that undergo palmitoylation, targeting MAP6 to the Golgi apparatus or plasma membrane (Cuveillier2021Beyond).

MAP6 has several isoforms, including MAP6-E and MAP6-N, which are produced through RNA splicing and alternative promoters. These isoforms exhibit different expression patterns and functions, with MAP6-N being prominent in neurons from birth to adulthood (Cuveillier2021Beyond). The protein's structure and function are further modulated by post-translational modifications such as phosphorylation, which can affect its microtubule-binding capabilities and interactions with other cellular components (Cuveillier2021Beyond).

## Function
MAP6, or microtubule-associated protein 6, plays a crucial role in the stabilization of microtubules and actin filaments, which are essential for maintaining cell structure and facilitating intracellular transport in healthy human cells. In neurons, MAP6 is involved in the regulation of actin cytoskeleton dynamics within dendritic spines, contributing to synaptic plasticity and cognitive functions. It is the first protein identified in dendritic spines capable of inducing actin bundling with periodic striations, protecting actin filaments from severing by cofilin, and enhancing myosin-mediated vesicular transport, which is vital for AMPA receptor trafficking and synaptic activity (Peris2018A).

MAP6's function is modulated by phosphorylation, which affects its translocation from microtubules to actin filaments in dendritic spines, a process necessary for maintaining spine density and synaptic plasticity (Peris2018A). The Mc modules of MAP6 are crucial for its ability to nucleate, stabilize, and bundle actin filaments, contributing to the structural plasticity of neurons (Peris2018A). MAP6 is also involved in neuronal development and function, interacting with various cellular compartments and proteins, including calcium channels, and influencing lysosomal transport (Cuveillier2021Beyond). Its role in synaptic plasticity is linked to its ability to mediate actin rearrangements necessary for synaptic modifications (Peris2018A).

## Clinical Significance
Mutations and alterations in the expression of the MAP6 gene are associated with several psychiatric and neurodevelopmental disorders, most notably schizophrenia. The MAP6 gene is located in a chromosomal region linked to schizophrenia susceptibility, and polymorphisms in this gene have been associated with the disorder (Volle2012Reduced; Fournet2010The). In schizophrenia patients, altered expression of MAP6 proteins is observed in the prefrontal cortex, a region critical for cognitive functions (Volle2012Reduced).

Animal studies have provided insights into the clinical significance of MAP6. Mice with reduced or deleted MAP6 expression exhibit behavioral and cognitive impairments that resemble symptoms of schizophrenia, such as social withdrawal, cognitive deficits, and hyperactivity (Gimenez20173D; Cuveillier2021Beyond). These mice also show abnormalities in neurotransmission, including increased dopamine overflow and imbalanced serotoninergic and glutamatergic systems, which are linked to schizophrenia-like symptoms (Fournet2010The; Cuveillier2021Beyond).

The MAP6 knockout mouse model has been used to study the neuroanatomical basis of these disorders, revealing structural brain changes such as reduced cerebellum and thalamus volumes, and defects in white matter tracts (Gimenez20173D). These findings suggest that MAP6 plays a crucial role in maintaining normal brain structure and function, and its dysfunction may contribute to the pathophysiology of schizophrenia and related disorders.

## Interactions
MAP6, also known as microtubule-associated protein 6, participates in various interactions with other proteins that are crucial for its function in neuronal connectivity and synaptic plasticity. MAP6 interacts with SH3 domain-containing proteins, such as intersectin1 and the p85 subunit of PI3K, which are involved in neuronal signaling pathways. These interactions are essential for coupling semaphorin 3E (Sema3E) receptors to PI3K, thereby activating the Akt pathway, which is crucial for axon growth (Deloulme2015Microtubuleassociated).

MAP6 also binds to a receptor complex composed of Plexin D1, Neuropilin1, and VEGFR2, which is important for axonal growth in subicular neurons (Deloulme2015Microtubuleassociated). The proline-rich domain of MAP6 is critical for these interactions, facilitating the recruitment and activation of SH2 and SH3 domain-containing proteins (Deloulme2015Microtubuleassociated).

In addition to its role in microtubule stabilization, MAP6 interacts with the actin cytoskeleton. It can bind to actin filaments, enhancing filament nucleation and forming stable filament bundles, which are crucial for synaptic plasticity and dendritic spine maintenance (Peris2018A). These interactions highlight MAP6's multifaceted role in maintaining neuronal structure and function.


## References


[1. (Gimenez20173D) Ulysse Gimenez, Benoit Boulan, Franck Mauconduit, Fanny Taurel, Maxime Leclercq, Eric Denarier, Jacques Brocard, Sylvie Gory-Fauré, Annie Andrieux, Hana Lahrech, and Jean Christophe Deloulme. 3d imaging of the brain morphology and connectivity defects in a model of psychiatric disorders: map6-ko mice. Scientific Reports, September 2017. URL: http://dx.doi.org/10.1038/s41598-017-10544-2, doi:10.1038/s41598-017-10544-2. This article has 25 citations and is from a peer-reviewed journal.](https://doi.org/10.1038/s41598-017-10544-2)

[2. (Cuveillier2021Beyond) Camille Cuveillier, Benoit Boulan, Charlotte Ravanello, Eric Denarier, Jean-Christophe Deloulme, Sylvie Gory-Fauré, Christian Delphin, Christophe Bosc, Isabelle Arnal, and Annie Andrieux. Beyond neuronal microtubule stabilization: map6 and crmps, two converging stories. Frontiers in Molecular Neuroscience, May 2021. URL: http://dx.doi.org/10.3389/fnmol.2021.665693, doi:10.3389/fnmol.2021.665693. This article has 23 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fnmol.2021.665693)

[3. (Deloulme2015Microtubuleassociated) Jean-Christophe Deloulme, Sylvie Gory-Fauré, Franck Mauconduit, Sophie Chauvet, Julie Jonckheere, Benoit Boulan, Erik Mire, Jing Xue, Marion Jany, Caroline Maucler, Agathe A. Deparis, Olivier Montigon, Alexia Daoust, Emmanuel L. Barbier, Christophe Bosc, Nicole Deglon, Jacques Brocard, Eric Denarier, Isabelle Le Brun, Karin Pernet-Gallay, Isabelle Vilgrain, Phillip J. Robinson, Hana Lahrech, Fanny Mann, and Annie Andrieux. Microtubule-associated protein 6 mediates neuronal connectivity through semaphorin 3e-dependent signalling for axonal growth. Nature Communications, June 2015. URL: http://dx.doi.org/10.1038/ncomms8246, doi:10.1038/ncomms8246. This article has 55 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/ncomms8246)

[4. (Volle2012Reduced) Julien Volle, Jacques Brocard, Mohamed Saoud, Sylvie Gory-Faure, Jérôme Brunelin, Annie Andrieux, and Marie-Françoise Suaud-Chagny. Reduced expression of stop/map6 in mice leads to cognitive deficits. Schizophrenia Bulletin, 39(5):969–978, September 2012. URL: http://dx.doi.org/10.1093/schbul/sbs113, doi:10.1093/schbul/sbs113. This article has 41 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1093/schbul/sbs113)

[5. (Peris2018A) Leticia Peris, Mariano Bisbal, José Martinez-Hernandez, Yasmina Saoudi, Julie Jonckheere, Marta Rolland, Muriel Sebastien, Jacques Brocard, Eric Denarier, Christophe Bosc, Christophe Guerin, Sylvie Gory-Fauré, Jean Christophe Deloulme, Fabien Lanté, Isabelle Arnal, Alain Buisson, Yves Goldberg, Laurent Blanchoin, Christian Delphin, and Annie Andrieux. A key function for microtubule-associated-protein 6 in activity-dependent stabilisation of actin filaments in dendritic spines. Nature Communications, September 2018. URL: http://dx.doi.org/10.1038/s41467-018-05869-z, doi:10.1038/s41467-018-05869-z. This article has 30 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41467-018-05869-z)

[6. (Fournet2010The) Vincent Fournet, Marion Jany, Véronique Fabre, Farah Chali, Didier Orsal, Annie Schweitzer, Annie Andrieux, Fany Messanvi, Bruno Giros, Michel Hamon, Laurence Lanfumey, Jean‐Christophe Deloulme, and Marie‐Pascale Martres. The deletion of the microtubule‐associated stop protein affects the serotonergic mouse brain network. Journal of Neurochemistry, 115(6):1579–1594, November 2010. URL: http://dx.doi.org/10.1111/j.1471-4159.2010.07064.x, doi:10.1111/j.1471-4159.2010.07064.x. This article has 27 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1111/j.1471-4159.2010.07064.x)